CA2294931A1 - .beta.-alkoxyacrylates against malaria - Google Patents

.beta.-alkoxyacrylates against malaria Download PDF

Info

Publication number
CA2294931A1
CA2294931A1 CA002294931A CA2294931A CA2294931A1 CA 2294931 A1 CA2294931 A1 CA 2294931A1 CA 002294931 A CA002294931 A CA 002294931A CA 2294931 A CA2294931 A CA 2294931A CA 2294931 A1 CA2294931 A1 CA 2294931A1
Authority
CA
Canada
Prior art keywords
compounds
phenyl
optionally substituted
lower alkyl
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002294931A
Other languages
French (fr)
Inventor
Robert George Ridley
Huegues Matile
Christian Hubschwerlen
Jawad Alzeer
Jacques Chollet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2294931A1 publication Critical patent/CA2294931A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to the use of .beta.-alkoxyacrylates of formulae (IA) or (IB) wherein R, R1, R6, R7, R8, X and Z are as defined herein, as therapeutically active substances, especially in the treatment or prophylaxis of malaria and to medicaments containing these substances.

Description

CA 02294931 1999-12-29 .
WO 99!02150 PCT/EP98/04162 j3-Alkoxyac~lates against malaria The invention relates to compounds of the general formulae R~
.~ X
O~R1 RIO
~O
R~O~X\ O Rs R or S
W
IA R Ra IB
wherein Rl is lower alkyl X is N or CH
R In TA 1S ~Y/ A Ial wherein Y is S or O and to A1 is phenyl, which may be substituted by one or more substituents, selected from halogen, lower alkoxy, lower alkyl, CFg, N02~ NH2 phenoxy or CFs-phenoxy; naphthyl; isothiazol-3-yl; thiazol-2-yl, optionally substituted by lower alkoxyalkoxyalkyl, lower alkyl, lower alkoxycarbonyl or lower acetoxyalkyl; thiadiazol-2-yl, optionally substituted by lower alkylthio, lower alkinylthio, cycloalkyl-alkylthio, CF3 or -NHC6H4CF3; quinoxalin-2-yl, optionally substituted by halogen or lower alkyl;
2o benzoxazol-2-yl; benzotriazine, optionally substituted by an oxo-group; and quinolin-2-yl;

~ O
Or R2 Ia2 wherein R2 is hydrogen, lower alkoxycarbonyl, CF3, lower alkyl, cycloalkyl, lower alkoxyalkyl, lower alkylthioalkyl or lower alkoxy and A2 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, CFg, halogen, lower alkylthio, lower alkoxy or N02;
-C(O)C6H5; -C(CH3)=CH-CgH4-lower alkyl;
-CH=CH-CgHS; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; thiazol-5-yl, optionally substituted by lower alkyl; thien-3-y1, optionally substituted by lower alkyl; thien-2-yl, optionally substituted by halogen; quinolin-2-yl; naphthyl, benzo[b]thiophen-2-yl, optionally substituted by lower alkyl or halogen; or benzo[b]furan-2-yl;

Or ~ W ~ Ia3 wherein W is S, O, NH or CH2;
R3 is hydrogen or lower alkyl and A3 is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran or phenyl, which may be substituted by one or more substituents, selected from halogen, CFg or lower alkyl;
Or ~ Ia4 wherein A4 is phenyl, which may be substituted by one or more substituents, selected from N02, lower alkoxy, halogen, CFg,phenyloxy, styryl-phenyl or (2-CFa- or Cl-phenyl)-furan-2-yl; benzo[1,3]dioxol-5-yl, optionally substituted by halogen; isoxazol-4-3o yl, optionally substituted by phenyl or Iower alkoxyalkoxy; quinolin-3-yl; pyridin-2-yl; pyridin-3-yl, pyridin-4-yl; furyl; thien-2-yl; thien-3-yl;
-C--__C-C(CH3)3; -C-_C-C6H5; indolizin-2-yl, optionally substituted by lower alkyl; benzofuran-2-yl; benzopyran-3-yl or dihydrobenzo [b] thiophen-5-yl;
Ra Or ~ ~ A Ia5 wherein 5 R4 is hydrogen or lower alkyl; and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, N02, halogen, cyano or CF3; pyridin-2-yl;
pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl;
io pyrrol-2-yl, optionally substituted by lower alkyl;
furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl;
thiazol-2-yl, optionally substituted by C gH4Cl;
thiazol-4-yl, optionally substituted by phenyl;
benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo [b] thiophen-3-yl;
Ia6 or wherein A6 is phenyl, optionally substituted by CF3;
Or ~ \ A Ia7 wherein A7 is phenyl, optionally substituted by CFg;
or -(CH2)n-A8 Ia8 wherein n is 4 and A8 is phenyl, which may be substituted by one or more substituents, selected from CFg, halogen or -CH=N-OCH2-CO-OCHg; naphthyl or pyridin-4-yl;
s ,. I ~ A9 Ia9 or 3o wherein A9 is phenyl, optionally substituted by CFg;
and wherein in formula IB
R6-R8 are hydrogen, lower alkyl or lower alkoxy and Z is hydrogen; lower alkoxy; lower alkyl; or halogen ~ B' or ~ Ibl wherein V is O, -N(CHg)-, -S- and B1 is phenyl, optionally substituted by halogen or alkyl; quinolin-8-yl; pyrimidin-2-yl; -CH(CHg)-C6H5; or -CH2-C6H5;
O
z or ~~~~CHz)m ~B Ib2 wherein l0 m is 0 or 1; and B2 is phenyl, optionally substituted by halogen, lower alkyl or CFg; or benzo[b]thiophen-5-yl;

or ~o~B3 Ib3 wherein 16 B3 is phenyl, optionally substituted by CFg;
~O~N~Ba or Rs Ib4 wherein R~ is hydrogen, lower alkyl or lower alkoxyalkyl and B4 is phenyl, optionally substituted by CF3; pyridin-20 2-yl; or thiazolin-5-yl, optionally substituted by lower alkyl;
or ~ B Ib5 wherein B5 is phenyl; -C=C-C(CHg)3; or thien-3-yl;
25 as well as pharmaceutically acceptable salts of compounds of formulae IA and IB. All possible stereoisomers as well as their racemates are included in formulae IA and IB.
It has now surprisingly been found that compounds of the present invention are useful against malaria. Every year, between 300 and 500 3o million people develop malaria. Close to 3 million people die as a result of this disease, most of them children and nearly all of them living in tropical Africa. Fifty years ago, many people thought that malaria could be completely eradicated. But over the past twenty years, malaria has been making a comeback. For years, chloroquine has been the standard treatment, but in some areas the malaria parasite is resistant to chloro-quine and to cocktails of almost all the older antimalarials. Around 40%
of the world's population now live in areas where malaria is found.
The compounds of the invention have the property that they are active not only against chloroquine-sensitive, but also against l0 chloroquine-resistant malaria pathogens. For this reason they are very well suited for the prophylaxis and treatment of malaria, especially in cases where the malaria pathogens are resistant to chloroquine.
Most of the above described (3-alkoxyacrylates and their salts are known compounds. They are described in the following documents EP
~5 379 098, EP 299 694, WO 9007493, EP 278 595, EP 463 488, EP 370 629, EP 475 158, EP 474 042, EP I78 826, DE 3 519 280, EP 433 233, EP 460 575 and EP 254 426 as compounds with fungicidal activity for use in agriculture.
The following compounds of formula IA5 are novel:
R~
i ~ ~
R ~O~ ~~O R4 As wherein R1 is lower alkyl, X is N or CH, R4 is hydrogen or lower alkyl and A5 is phenyl, which may unsubstituted or substituted by one or more substituents, selected from lower alkyl, lower alkoxy, N02, halogen, cyano or CFg; pyridin-2-yl; pyridin-4-yl;
quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yi; thien-2-yl;
thien-3-yl, optionally substituted by halogen and lower alkyl; thiazoi-2-yl, optionally substituted by C gH4Cl;
thiazol-4-yl, optionally substituted by phenyl;
benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo[b]thiophen-3-yl;
as well as their pharmaceutically acceptable salts.
Objects of the present invention are the use of the mentioned compounds of formulae IA and IB and their pharmaceutically acceptable salts thereof against chloroquine-sensitive and chloroquine resistant malaria pathogens, the use of these compounds for 1o manufacture of corresponding medicaments, medicaments, containing these compounds and their salts as well as new compounds of formula IA5 per se.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a straight or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and the like.
2o The term "halogen" denotes chlorine, iodine, fluorine or bromine.
The term "lower alkoxy" denotes an alkyl group, as defined earlier which is attached via an oxygen atom. The term "cycloalkyl" denotes saturated cyclic hydrocarbon residues containing 3 to 6 carbon atoms.
The present invention embraces all possible racemates and their optical antipodes.
Preferred compounds of formula IA are especially those of formula IAS, R' O~
R~O~X~ O R4 ~ A5 _7_ in which R1 is methyl, X is CH, R4 is hydrogen and A5 is phenyl, substituted by one or more substituents, selected from CFg, bromine, chlorine, methoxy, N02 or lower alkyl; or naphthyl or thienyl.
Compounds of formula IA2 R~
O~
R~O~X~ O

O~N~A
/ 'IYR2 in which R1 is methyl, X is CH, R2 is hydrogen or lower alkyl and A2 is phenyl, substituted by CFg, chloro, fluoro, methyl, t-butyl or SCHg are also preferred.
Another group of preferred compounds is the following:
R' O~

R~O~X~ O

A~
\ ~Y~

IAl in which R1 is methyl, X is CH, Y is O or S and A1 is phenyl, optionally substituted by methyl, isopropyl, t-butyl, bromo, chloro, CFg or methoxy; naphthalenyl; or thiadiazolyl, optionally substituted by thiomethyl or propynylthiocyclopropyl.
The following intermediates which are used in the process for preparation of compounds of formulae IA4 show also a pharmaceutical activity against malaria pathogens:
O~CH3 H3C~0 \ O
\ Br /
II

_g_ ~CH3 H3C~0 O
III and ~CH3 H3C~
O
The compounds of formulae IA and IB can be prepared as described in the documents cited above.
In addition, compounds of formulas IA1-IA9 and IB1-IBS, can be prepared in accordance with schemes 1-14.
Scheme 1 iRi ~R1 O

RwOiX~ O Rv0 I ~ Br A
AIYI--I --VI

wherein the substituents have the significances described above.
Scheme 2 O~

V A~ ~ R~O~XW O
,C=NOH
R2 ~ ,N A2 ~O
VII ( / R2 _g_ wherein the substituents have the signifcances described above.
Scheme 3 O~Rt O~R~

R O \ O R~O~x\ O R3 _ 'Sn ~ OTHP
~ 'OTHP
x T'HP=tetrahydro-pyran ~R
O Rt R
Rt X Oi O '~. O R R~O~x\ R3 Rv iX O
O Q \ R3 A s v ~ \ Br i-- ~ ~ OH
x>I ~ i XI
wherein the substituents have the significances described above.
Scheme 4 R~
'R~
O R~ X
RvOiX\ wOi \ w0 \ 4 \ ' O P + A4CH0 -->~ \
'' ~ OCH3 XIII

wherein the substituents have the significances described above.
Scheme 5 R

R~O~) \ CHO A5 XIII + A5 \
Ra wherein the substituents have the significances described above.

Scheme 6 Br As Br As~Br XV XVI
t of OAR
RvO~ R' X
~O~ ~ ~O
XVI + s ---~ ~ \ ~ ~ A

wherein the substituents have the significances described above.
Scheme 7 Rj Br ~.~Br XVII R\
Br A -~ O
XVIII XIX

wherein the substituents have the significances described above.
Scheme 8 R>
R
O
i R~O~ --~ R~O~Xy O

~/ ~/

XX
wherein the substituents have the significances described above.

Scheme 9 , R, R\ RvO~ As O HzSOa As ~", NazS
~I IA9 wherein the substituents have the significances described above.
Scheme 10 O~R1 R1 R~p~X~ O RvO~
+ B1~ -~y i XXIII
S
IBi XXII
wherein the substituents have the significances described above.
Scheme 11 R~
O~
R~O~X~ O
O
XXII + B2-(CHz)m OH
~O (CHZ)m ~
XXIV S

wherein the substituents have the significances described above.

Scheme 12 Rt O~
O R~OiX~ O
XXII + g3~0iH O
i XXV . S / O~g3 wherein the substituents have the significances described above Scheme 13 ~Rt O
t R~ ~X\ _ XXII + B~N~O~H ~ O ~O
Rs i ~ O~yBa XXVI S
Rs wherein the substituents have the significances described above.
Scheme 14 Rt U ~Rt t R~O~ \ O Rt ~O~
i ~O + BSCHO ---s S / ~ /P\OCH XXVIII g -- OCHg XXVII

wherein the substituents have the significances described above.
The novel compounds of formula IA5 can be prepared in z0 accordance with scheme 5 and by Examples 164-206.

As mentioned earlier, the [3-alkoxyacrylates of general formulae IA
and IB in accordance with the invention and their pharmaceutically usable salts have valuable pharmaceutical properties.
In particular, they have a very good activity against malaria pathogens. Their activity is equally good against chloroquine-resistant strains of the pathogen as against chloroquine-sensitive strains.
Accordingly, the present compounds can also be used for the prophylaxis and cure of malaria even in those cases where the pathogen does not respond to chloroquine.
to In the following table are described the tested compounds:
R' O~
i R~O~X~ O
A~
~Y~

R1 X Y A1 Expl.No.
CH3 -CH S c\ ~, 1 I~
CH3 CH S I w F 2 CH3 -CH S ~~ 3 I~
CH3 -CH S I ~ ~ 4 CH3 -CH S I ~ 5 CH3 _CH S
CH3 CH S I ~ 7 CHg -CH S ~ CF, I
NOZ
CH3 CH S I ~ a' CH3 CH S I ~ 10 F
F
F
CH3 CH S I ~ o~ 12 CH3 CH S I ~ 13 I~
CH3 CH S I ~ 15 CFA
CH3 CH S i ~ cF' 16 N
(~(CHZjr-O-(CH:)rOCH~
~S

CH3 CH S S~S 18 NN
CH3 CH S ~~S~H 19 N
CH3 CH S ~5~~, 20 NON
CH3 CH S 1i ~~oF, 21 N

1i ~-N~ 22 N"~N H ~ I

CH3 CH S / ~ ~~ 23 N \
~N
CH3 CH S ~ ~ o,~ 24 CH3 CH S ~ ~ 0 25 CH3 CH S N ~ ~ 28 CH3 CH O N~N I \ 27 ~N /
O
CH3 CH O N~ \ B' 28 N /
CH3 CH O ~N~ \ B' 29 CH3 CH O \ ''~ 30 I
N

CH3 CH O N~ ~ 31 N
CH3 CH O ~ 32 N
CH3 CH O i'~ 33 CH3 CH O ~ 34 I
Preferred compounds are also those of formula IAl wherein Rl is methyl, X is CH, Y is S or O, A1 is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, lower alkyl, CFs, NOa, NHz, phenoxy, or CFa-phenoxy. Such compounds can be prepared according to the procedure set in example 1 of EP 278595, Iike the following specific compounds:
(E)-2-[2-(2-Bromo-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
to (E)-3-methoxy-2-[2-{4-phenoxy-phenoxymethyl)-phenyl]-acrylic acid methyl ester;
(E)-3-methoxy-2-[2-[4-(4-trifluoromethyl-phenoxy)-phenoxy-methyl]-phenyl]-acrylic acid methyl ester;
(E)-3-methoxy-2-[2-(4-methoxy-2-nitro-phenoxymethyl)-phenyl]-15 acrylic acid methyl ester;
(E)-2-[2-(2,4-dibromo-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-2-[2-(2-chloro-4-methyl-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
20 (E)-2-[2-(2-chloro-4-trifluoromethyl-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-3-methoxy-2-(2-pentafluorophenyloxymethyl-phenyl)-acrylic acid methyl ester;

(E)-2-[2-(2,4-dichloro-phenylsulfanylmethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-2-[2-(2-amino-4-trifluoromethyl-phenylsulfanylmethyl)-- phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-2-[2-(2-amino-4-methoxy-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester;
(E)-2-[2-(4-tert-butyl-2-chloro-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester.
R' O~
i R~O~X~ O

O, \~ A

~ R lA2 R1 X RZ A2 Expl.No.
CH3 CH -C(O)OCH3 I ~ 36 CH3 CH CF3 ~F, 37 I~
CH3 CH CH3 C~ 38 I~
CH3 CH -(CH2)2CH3 I ~ 39 cF, CH3 CH -~ I ~ 40 CHs CH -a I ~ 41 N

CHs CH -CH20CHs ~ ~ 42 N
CH3 CH CH3 CF, 43 (~
°~
CHs CH CHs ~F' 44 i~
s~
CHs CH H ~ 45 I ' CHs CH CH2CHs I ~ 46 ~N
CHs CH CHs I ~ 47 CHs CH CH3 °~ 48 I~
CHs CH CH2CHs ~' 49 I~
CHs CH CH2CHs I ~ F 50 CHs CH CHZCHs I ~ B~ 51 CHs CH CHs 52 I w I
CHs CH CHs I ~ 53 CH3 CH CH3 °F' - 54 I~
F

l~
CH3 CH CHs F 56 I~
F

I~
F
CH3 CH CH2CH3 I ~ 58 F

CH3 CH CH2SCH3 I ~ 60 CHg CH CH3 °~ ~ 61 I
CH3 CH H I ~ 62 CH3 CH H ~ ~ 63 CH3 CH H I ~ 64 CH3 CH H I ~ e~ 65 CH3 CH H I ~ 66 CHs CH CH2CHs I ~ ~ 67 CHg CH H I ~ No2 CHs CH CHs I w 6g CHs CH CHs I ~ 70 CHs CH H I ~ 71 F
CHs CH H F 72 I~
CHs CH CHs I ~ 73 CF, CHs CH CHs I ~ 74 CHs CH CHs I ~ 75 No2 CHs CH CH3 S \ ~ 76 CHs CH CH3 S ~ ~ o~ 77 CHg CH CH3 I ~ CH, 78 CHs CH CHs I ~ 7g CHs CH CHs ~' gp CHs CH CHs ~ ~ gl CHs CH CHs ~ N~ 82 CHs CH CHs ~ 'N 83 CHs CH CHs ~ S ~~ 84 CH3 CH CHs ~S g5 N

CHs CH CHs ~ ~ ~ 86 CHs CH H ~ ~ o~ g7 CHs CH CHs ~ ~ gg CHs CH CHs I ~ o' gg CHs CH CH2CHs I ~ o' 90 CHs CH (CHZ)2CHs ~ ~ 91 CHs CH -~ ~ ~ 92 CHs CH CHs ~ ~ 93 CHs CH CHs ~ ~ 94 CHs CH H I ~ ~F' 95 CHs CH CF3 I w 96 CHs CH CHs N°2 I~
CHs CH H ~ ~ gg CHs CH H i ~ 99 CHs CH H ~ 'N 100 CHs CH CHs ° 101 CHs CH H I ~ 102 ~CL
CI
CHI CH H ~ ~ 103 I
N
CHs CH CHs ~ ~ 104 CHs CH CHs ~F' 105 I~
CFA
CHs CH CH3 F I ~ 106 CHs CH CHs I ~ F 107 F
CHs CH CHs F 108 I~
F

CH3 CH CH3 ~ F 109 I~
F

CH3 N CH3 I ~ 110 ~CF~

CHg N CHg cF, 111 f~
CFA

CH3 N CF3 f ~ 112 CH3 N CHg ~NO~ 113 I~

CH3 N CH3 I ~ 114 CH3 N CH3 i ~ ~ 115 CH3 N CH3 I ~ ~ 116 CHg N CH3 I ~ c~ 117 of R' O~
X
RvO~ W O R3 \ \ W.As R1 X R3 W A3 Expl.No.

F
I
F
F

I w I' i CH3 CH H2 S I ~ 120 /
CFA
CH3 CH H2 S ~ cF' 121 /

I ~ I' /
CH3 CH H2 NH I ~ 123 /
CH3 CH H2 NH I ~ ~F, 124 /

I
Preferred compounds are also those of formula IA3 wherein Rl is methyl, X is CH-, R3 is H2, W is S, O, A3 is phenyl, which may be substituted by one or more substituents, selected from hal, CFa, lower alkyl or is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran. Such compounds can be prepared according to the procedure set out in example 118, like the following additional compounds:
(E)-2-[2-[(E)-3-(5-Acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran-2-yloxy)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[{E)-3-(2-chloro-phenylsulfanyl)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(E)-3-(2-chloro-4-methyl-phenoxy)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester, and to (E)-2-[2-[(E)-3-(2-chloro-4-trifluoromethyl-phenoxy)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester.
R
R' ~O
a Rl X A4 Expl.No.

CH3 CH ~ ~ 126 I ~ E/E

NOz CH3 CH ~ ! 127 E/Z

NOZ

CH3 CH I ~ ~ 128 No, E/Z

CHs CH \ , ___ 129 I~

No, E/E

CH3 CH ~ c~ 130 I~
c.
CH3 CH I ~ 131 "°2 E/E
CH3 CH i ~ 132 "oz E/Z
CH3 CH F I w 133 CH3 CH c~ I w 134 i °~
CH3 CH '~ I ~ 135 c.
CH3 CH I ~ °~ 136 CH3 CH ° 0 137 I~
c.

I ~ I
i CHg CH I ~ cF' 139 CFA
CH3 CH I ~ 140 CH3 CH ~" ~ 141 I ~N
O~'~.O/

CH3 CH ~ ' 142 / o/

CH3 CH ~ ~ ~ 143 CH3 CH ~ ' ~ ~ 144 / ' CHg CH ~ ' N' 145 /

CH3 CH ~ ' 146 /
No, E/E

CHg CH ~ ' 147 /
No, E/Z

CH3 CH ~ ' 148 / CFA

cH3 CH i ' ~ 149 /o CH3 CH ' ' 150 N /

CH3 CH ~ 'N 151 /

CH3 CH ~ ~ 152 CH3 CH ~ ' I53 /

CH3 CH ~ ~ 154 CH3 CH ~ ~ 155 CH3 CH ~ 156 CH3 CH ~ ~ 157 CH3 CH N\ ~ 158 CH3 CH ~ ~ 159 CH3 CH o ~ ~ 160 CH3 CH ~ ~ 161 CH3 CH - ~ ~ 162 CH3 CH ~ ~ ~ 163 Preferred compounds are also those of formula IA4 wherein Rl is methyl, X is CH, and A4 is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, NOa, styryl-phenyl, or (2-CFs-, or Cl-phenyl)-furan-2-yl. Such compounds can be prepared according to the procedure set in example 126 (EP-475158 A2 920318), like:
(E)-3-Methoxy-2-[2-[(E)-2-[5-(2-trifluoromethyl-phenyl)-furan-2-yl]-vinyl]-phenyl]-acrylic acid methyl ester, (E)-2-[2-[(E)-2-(2-chloro-3,4-dimethoxy-6-vitro-phenyl)-vinyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(E)-2-[5-(2-chloro-phenyl)-furan-2-yl]-vinyl]-phenyl]-3-methoxy-acrylic acid methyl ester and (E)-3-methoxy-2-[2-[(E)-2-[(E)-4-styryl-phenyl]-vinyl]-phenyl]-acrylic acid methyl ester.
_R~
R~Oi IAS
R1 R4 A5 X Expl.No.

CH3 H I ~ o-CH3 H ~ ~ ~ CH 165 CH3 H ~ ~ CH 166 N

CH3 H i ~ CH I67 c.

CH3 H ~ ~ CH 168 F
F

CH3 H ~ ~ ~ CH 169 N

CH3 H ~ ~ ~ CH 170 CH3 H ~ ~ N CH 172 CH3 H ~ CH 173 CH3 g ~ S CH 174 i CH3 H ~ ~ CH 175 CH3 H ~ ~ ~ CH 176 CH3 H ~ ~ ~F' CH 177 CH3 H ~ ~ F CH 178 CH3 H ~ ~ w CH 179 CH3 H ~ ~ ~ CH 180 F

CH3 H ~ ~ CH 181 CFA

CH3 H ~ ~ CH 182 CH3 H ~ ~ ~ ~ , CH 183 N

CH3 g ~ ~ CH 184 C.

CH3 H ~ ~ CH 185 CFA

F

CH3 H ~ ~ CH 187 S
N

CHg H I % B, CH 188 CH3 H I ~ ~ CH 189 CHg H I 5 CH 190 CH3 g ~ ~ CH 191 CH3 g CH 192 I~

I~

CH3 H I ~ ~ CH 194 CHg H I S CH 195 CHg H I ~ \ CH _ _ 196 CH3 H I ~ CH 197 F3 CH _ i9g I~
CFA

CH3 H I ~ cF, CH 199 CF, CH3 H I ~ CH 200 CH3 H I ~ ~ CH 201 CH3 H I ~ CH 202 CH3 H I ~ CH 203 CHg H o' ~ CH 204 I w \_ CHg H I ~ N 206 CF, Preferred compounds are also those of formula IA5 wherein Rl is methyl, X is CH, R4 is H and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NOz, hal, cyano, or CFs. Such compounds can be prepared according to the procedure set out in example 164, like:
(E)-2-[2-[( lE,3E)-4-(2-Chloro-3,4-dimethoxy-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(2-bromo-4,5-dimethoxy-phenyl)-buta-1,3-1o dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[( lE,3E)-4-(2-cyano-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-3-methoxy-2-[2-[( lE,3E)-4-(3-methoxy-2-nitro-phenyl)-buta-1,3-dienyl]-phenyl]-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(4-fluoro-2-trifluoromethyl-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(4-tert-butyl-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(2-chloro-4-fluoro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(lE,3E)-4-(2,4-difluoro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(1E,3E)-4-(2-chloro-4-methyl-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[2-[(iE,3E)-4-(2,4-dimethyl-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester and (E)-2-[2-[(lE,3E)-4-(2-fluoro-4-trifluoromethyl-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester.
R' O~
R~O~X~ O
As i R1 X A6 Expl.No.

CH3 N' ~ ~ 207 CFA

CH3 N ~ ~ F' 208 CFA

R' O
R~Oi ~ O
A~

R1 X A7 Expl.No.

CH3 N ~ ~ 209 cF, O
R~O~X~ O
Aa v v R1 X A$ Expl.No.

CH3 CH ~ ~ 210 CFA

CH3 CH ~ ~ cF' 211 CH3 CH ~ ~ 212 CH3 CH ~ 'N 214 CH3 N ~ ~ 215 CHg N ~ ~ 216 ~ o N

O~

~0~~

R1 X A9 Expl.No.

CH3 N 1 ~ 217 O ~

i R~ ~X

O ~ O

B' w i V

S ~ ~

R1 V B1 X Expl.No.

CH3 -p- E ~ ~ CH 218 / N~

CH3 -p- ~ ~ CH 219 CH3 -N(CH3)- ~ ~ CH 220 CH3 -N(CH3)- CH 221 CH3 -N(CH3)- CH 222 CH3 -N(CH3)- ~ ~ CH 223 N

R' O~
R~
~O
O

O~~CH2)m ~

R1 B2 X m Expl.No.

CHg I ~ of CH 1 225 CH3 ~ ~ CH 0 226 F

CH3 ~ ~ CH 0 227 CH3 ~ ~ CH 1 228 c.

CH3 ~ ~ CH 1 229 CH3 ~ ~ CH 1 230 CH3 I ~ c~ CH 1 231 c.

CH3 ~ ~ \ CH 1 232 CH3 ~ ~ CH 1 233 c~

CH3 ~ ~ ~' CH 0 234 CH3 ~ ~ ~F' CH 1 235 O~

R~O~X~ O
O
~~ B3 R1 B3 X Expl.No.

CH3 ~ ~ CH 236 CFA

R~
O~
R~O~X~ O
O~ \~Ba RS

R1 R5 B4 X Expl.No.

CH3 ~o~ ~ ~ CH 237 CH3 CH3 ~ ~ CH 238 ~CF~

CH3 CH3 ~ ~ CH 239 N

CH3 g S~ CH 240 ' ~N

R' R~O~:

R1 B5 X Expl.No.

CH3 ~ ~ CH 241 CH3 ~ CH 242 CH3 ~ ~ CH 243 R~
R~ IB
R1 Z R6 R7 R8 Expl.No.

CH3 ~~ H H H 244 CH3 Br H H H 246 CH3 Cl H H H 249 CH3 H H H CHs 250 The activity of the compounds against not only chloroquine-resistant, but also chloroquine-sensitive malaria pathogens shows itself in a strong, in vitro measurable growth inhibition of various strains of the human-pathogenic Plasmodium falcvparum, as set forth in Table 1 hereinafter. The ratio of the growth inhibition of a strain which is especially resistant to chloroquine and of a strain which is sensitive to chloroquine gives as the "resistance index" a measurement for the absence or presence of a cross-resistance with chloroquine. Since, for all to novel compounds the resistance index lies between 0.7 and 2.5, they inhibit the growth of sensitive as well as resistant strains of the malaria pathogen equally effectively. They are accordingly also suitable for the prophylaxis of a malaria disease and also for the treatment of a malaria disease even when chloroquine is ineffective.
The good activity against malaria pathogens is also shown in animal experiments. The effective doses measured after oral and subcutaneous administration to mice infected with malaria pathogens are shown in Table 2 hereinafter.
Test method for the determination of the activity against 2o Plasmodium falc~arum in vitro The preparations are tested on intraerythrocytary stages of Plasmodium falciparum from asynchronous cultures according to the method of Desjardin et al. (Desjardins, R.E. et al: Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 16, 710-718, (1979)).
The culture medium consists of RPMI 1640 with the addition of 25 mM HEPES, 25 mM NaHC03, 100 ~.g/ml neomycin and 10°lo human serum (A+). Human-A+ erythrocytes are used as the Plasmodium falciparum host cells. The parasites are maintained at 37~C in an atmosphere of 3% 02, 4% C02, 93% N2 and 95% relative humidity.
In order to determine the activity, the preparations are dissolved in DMSO, pre-diluted in the culture medium to a suitable starting concentration and subsequently titrated-out an to microtitre plates in the 2nd stage over 6-7 steps. After the addition of the parasite culture (0.7% parasitemia in 2.5% erythrocyte suspension) the test plates are incubated under the conditions given above for 72 h. The parasite growth in the different preparation concentrations is determined using to [G-3H]-hypoxanthin incorporation compared to untreated control cultures on the same test plates. The 50% growth inhibition (ICSp) is calculated according to logit regression analysis from the resulting dosage-activity curve.
The preparations are tested on at least one chloroquine-resistant and one chloroquine-sensitive Plasmodium falciparum strain.
Additional sensitive and resistant strains are included for father characterization.
Test method for the determination of the activity a ainst Plasmodium berghei in vivo 2o The preparations are tested on mice infected with malaria pathogens (Plasmodium berghei). Male albino mice (IBM:MORO(SPF), FUELLINSDORF) weighing about 25 g are used as the test animals.
They are kept in climatized rooms at 21-22~C in groups of 5 animals per cage. They receive ad libitum a diet feed with a low PABA content (NAFAG FUTTER " No. 9009 PAB-45, PABA content 45 mg/kg) and drinking water. On the first day of the test (DO) the test animals are infected with Plasmodium berghei (strain ANKA). For this there is used heparinized blood of a donor mouse with about 30% parasitemia, which is diluted with physiological saline such that it contains 108 parasitized erythrocytes per ml. 0.2 ml of this suspension is injected intravenously (i.v.) into the mice to be treated and into the control mice.
In untreated control animals the parasitemia normally reaches 30-40%
on the third day after the infection (D+3) and the test animals die between days +5 and +7.

The substances to be tested are dissolved or suspended in distilled water or in a mixture of 7% Tween 80, 3% alcohol (96%) and water.
Usually, 0.25 ml of this solution or suspension is administered once subcutaneously and perorally to groups of 5 test animals. Treatment is effected 24 hours after the infection. 10 control animals are treated in the same manner with solvent or suspension medium per test.
All substances are tested in a first test in a single dosage of 100 or mg/kg. Only those substances which in this test ( 10 mg/kg) have shown a parasitaemia reduction of more than 90% are used for the l0 titration. Suitable dilutions of the test substance can be used to obtain an accurate titration of the activity.
48 hours after the treatment (D+3) blood smears are prepared from all animals using blood from tail veins and are stained with giemsa. The average erythrocyte infection rate (parasitemiea in %) in the control groups as well as in the groups which have been treated with the test compounds is determined by counting under a microscope.
The difference in the average values of the infection rates of control group (100%) and treated groups is calculated and expressed as a percentage reduction (GI%). The EDSp or EDgp is determined 2o mathematically by means of the JMP programme (nonlinear fit). The EDSp (EDgp) in mg/kg is that dose which after single administration reduces the average erythrocyte infection rate by 50% (90%) in comparison to the control group.

Table 1 Values measured in vitro (ICSp values in ug/ml) for the grouth inhibition of the human-pathogenic Plasmodium falciparum strain NF54 as an example of a chloroquine-sensitive strain and of the human-pathogenic Plasmodium flaciparum Kl as an example of a chloroquine-resistant strain.
Formula Example in vitro No.

strain NF 54 strain Kl ICSp 72 h ICSp 72 h IAl 11 1.17 4.9 IAI 28 17.7 19.1 IA2 105 0.21 1.01 IA2 110 20 65.8 IA2 111 1.6 4.3 IA3 120 1.75 2.51 IA4 126 1.2 3.3 IA4 136 1.04 2.9 IA5 185 0.06 0.15 IA5 199 0.06 0.13 IA5 203 0.07 0.28 IA5 206 0.4 1.4 IA6 207 10.8 25.8 IA7 209 3.21 5.7 IA8 210 0.85 1.35 IA8 211 0.33 1.34 IA9 217 23.7 60.8 IB 1 222 22,6 64.3 IB4 238 17.5 40.9 IB5 241 1.4 7.4 -IB5 243 6.7 22.6 IB 244 147.3 419.2 IB 250 184.4 550.3 IB2 233 29.5 67.3 IB3 236 44.2 174.7 III 251 64.9 - 111 Table 2 Activity measured in vivo against Plasmodium berghei in mice in percentage reduction of the parasitemia after a perorally (po) or subcutaneously (sc) administered dose of 100 (10) mg/kg of test substance, EDSp is the effective administered dose of test substance Formula Example No. in vivo po act. % sc act. %

IAl 11 80 tox IA4 136 40 tox IA5 185 99.0 (10 mg/kg) 99.95 IA5 199 100 (10 mg/kg) 99.97 IA5 203 76 (10 mg/kg) 90 IA8 211 59 (10 mg/kg) 92 The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula IA or IB can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or nasally.
The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyois and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like.
Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula IA or IB or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their manufacture which comprises bringing one or 1o more compounds of formula IA or IB and/or pharmaceutically acceptable acid addition salts thereof into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of general formula IA
or IB as well as their pharmaceutically acceptable acid addition salts can be used for the treatment or prevention of malaria and, respectively, for the production of corresponding medicaments. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in a range of about 10 mg to about 2.5 g 2o per day of a compound of general formula IA or IB or the corresponding amount of a pharmaceutically acceptable acid addition salt thereof, although the upper limit can also be exceeded when this is found to be indicated.
In the following Examples, which illustrate the present invention but are not intended to limit its scope in any manner, all temperatures are given in degrees Celsius. The 250 MHz-1H-NMR spectra were measured at room temperature; chemical shifts $(ppm) relative to 8(TMS) = 0.0 ppm.
The novel compounds of formula IA5 can be prepared as described 3o below. .All temperature are given in °C.

Example 164 ~E)-2-[2-(1E.3E)-4-[4.5-Dimethoxy-2-nitro-phenyl)-buta-1,3-dienyll-phenyll-3-methoxy-acrylic acid methyl ester a) At room temperature, NaOCHg (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C.
Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50°
for overnight, the mixture was poured over water, and extracted with 1o ether, washed with brine and dried over MgS04. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-1. MS (EI): 237 (M).
b) At 0°, NaH (40 mg, 0.954 mmol) was added to a solution of (E)-2-[2-(dimethoxy-phosphorylmethyl)-phenyl]-3-methoxy-acrylic acid 2o methyl ester (EP-203606) (250 mg, 0.79 mmol) in THF (5 ml). The mixture was stirred at room temperature for 30 min and treated with (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (189 mg, 0.79 mmol) in CH2C12 (2 ml). After the mixture was stirred at room temperature for 3 h and refluxed for 1.5 h, the reaction mixture was cooled to room temperature and treated with CHgC02H (1 ml). After stirring for 10 min at room temperature, the reaction mixture was extracted with ethylacetate, washed with NaHCOg solution, brine, water, and dried over MgS04. Evaporation of the solvent and chromatography (hexane/ethylacetate 1:1) gave (E)-2-[2-(lE,3E)-4-[4,5-dimethoxy-2-3o nitro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester (116 mg, 34%) as white solid, m.p. 198-200°. IR (KBr): 1710, 1630 cm-1. MS (EI): 425 (M).
According to the procedure set forth in the preceding example, the following compounds were prepared:

Example 165 (E)-2-f2-f(IE.3E)-4-(2.4-Dichloro-phenvl)-buta-13-dienYll phenyll 3 methoxv-acr~ic acid methyl ester m.p. 143-145°
IR (KBr): 1707, 1629 cm-1, MS (EI): 388 (M).
Example 166 Methyl (E and/or Z)-3-rnethoxv-2-fo-f(all-E)-4-(2-p ridvl)-13-butadienyllphenyllac late m.p. 106-108°
1o Example 167 Methyl (E and/or Z)-2-fo-f(all-E)-4-(2 3-dichlorophenvl)-1,3-butadiene phenvll-3-methoxyacrvlate m.p. 141-145°
Example 168 Methyl (E and/or Z)-2-fo-f(all-E)-4-(2 3-difluorophenyl)-13-butadienyll-phenvll-3-methoxyacrvlate m.p. 142-144°
Example I69 Methyl (E and/or Z)-3-methoxy-2-fo-f(all-E)-4-(2-quinolinyl)-1 3 butadienyllphenvllacryiate m.p. 137-138°
Example 170 Methyl (E and/or Z)-3-method-2-fo-f(all-E)-4-(1-naphthyl)-1 3-butadien~ll phenyll ac late m.p.138-140°

Example 17I
Methyl (E and/or Z)-3-methoxy-2-fo-f(all-E)-4-(1-meth~Ipvrrol-2-yl)-1 3-butadienvllphen ly lac late m.p. 139-142°
Example 172 Methyl (E and/or Z)-3-methoxy-2-fo-f(all-E)-4-(4-pyridyl)-1,3-butadienyllphenyllacrylate m.p. 175-177°
Examine 173 to Methyl (E and/or Z)-2-fo-f(all-E)-4-(2-furvn)-13-butadienyllphenyll-3-methoxvacrylate m.p. 136-137°
Example I74 Methyl (E and/or Z)-3-methoxy-2-fo-f(all-E)-4-(2-thien~l)-1,3-butadienvll phenynl acrvlate m.p. 142-145°
Example 175 Methyl (E and/or Z)-3-methoxv-2-fo-f(all-E and/or Z)-4-(3-thienyl)-1.3-butadienyllphenyllacrylate 2o m.p.194-195°
Example 176 Methyl (E and/or Z)-3-methoxy-2-fo-f(all-E)-4-(3-auinolinyn)-1,3-butadienyl~~phenyll-3-methoxyacrylate m.p. 173-1?5°

Example 177 Methyl (E)-3-methoxy-2-!o-fall-E)-4-(alphaaalpha alpha-trifluoro=p-tolvl)-1.3-butadienvl]phenyll acrylate m.p. 190-I91°
Example 178 Methyl (E)-2-fo-f(all-E)-4-(p-fluorophenyl)-13-butadienyllphenvll-3-methoxvacrylate m.p. 156-157°
Example 179 to Methyl (E)-2-fo-f(all-E)-4-(o-ethoxyuhenyl)-13-butadienyllphenyll-3-methoxyacrvlate m.p. 152-153°
Example 180 Methyl (E)-2-fo-f(all-E)-4-(2-chloro-6-fluorophenyl)-1 3-butadienyllphenyllacrylate m.p. 165°
Example 181 Methyl (E)-3-methoxv-2-!o-!(all-E)-4-(aloha alpha alpha-trifluoro-m-tolvl)-1 3-butadienvllphenyllacrylate 2o m.p.152-153°
Examgle 182 Methyl (E)-2-fo-!(all-E)-4-(3-furyl)-1 3-butadienyl~phenvll-3-methoxvacrylate m.p. 174-175°

Example 183 Methyl (E)-2-fo-f(all-E)-4-f2-(p-chloro-phenyl)-4-thiazolyll-1 3-butadienv!!phenyl!-3-methoxyacrylate m.p. 167-171°
Example 184 Methyl (E)-2-fo-f(all-E)-4-(o-chlorophenvl)-1 3-butadienyllphenyllacrylate m.p. 158-162°
Example 185 1o Methyl (E)-3-methoxy-2-fo-f(all-E)-4-(alpha alpha alpha-trifluoro-tolyl)-1,3-butadienyllphenyll acrylate m.p. 148-149°
Example 186 Methyl (E)-2-fo-f(all-E)-4-(m-fluorophenvl)-1 3-butadienyll~henyll-3-methoxyacrylate IR (KBr): 1705, 1628 cm-1, MS (EI): 338 (M) Example 187 Methyl (E)-3-methoxv-2-fo-f(all-E)-4-(5_phenyl-4-thiazolyl)-13-butadienyll phenyl! acr~ate 2o m.p.167°
Example 188 Methyl (E)-2-fo-f(all-E)-4-(5-bromo-2-thienyl)-1 3-butadieny~phenyll-3-methoxvacrvlate m.p. 160-161°

Example 189 Methyl (E)-3-methoxv-2-fo-f(all-E)-4-(p-metho henvl) 13 butadienyll phenyll acrylate m.p. 164-166°
Example 190 Methyl (E)-3-methoxy-2-fo-f(all-E)-4-f3-methoxybenzofblthiophen 2 yll L3-butadienyljphenyll acrylate m.p. 202-203°
Example 191 o Methyl (E)-3-methoxv-2-fo-f(all-E)-3-(2-thiazolyl)-13-butadienvllphenvll acrvlate m.p. 131-133°
Example 192 Methyl (E)-3-methoxv-2-fo-f(all-E)-4-(5-methyl-2-thien ly )-13-15 butadienyllphenyllacrylate m.p. 131-I33°
Example 193 Methyl (E)-3-methoxy-2-fo-f(all-E)-4-(3-methyl-2-thien.,yl)-1 3-butadien ~~11 phenvll acrylate 2o m.p.168°
Example 194 Methyl (E)-3-methoxy-2-fo-f4-(2-na~hthyl)-1 3-butadien ~~llphen~illacrvlate m.p. 172°

Example 195 Methyl (E)-2-fo-f(all-E)-4-benzofblthiophen-2-yl-13-butadienvllphenyll-3-methoxy-acrylate m.p. 223-225°
Example 196 Methyl (E)-2-fo-f(all-E)-4-benzo lthiophen-3-yl-1,3-butadienvllphenvll-3-methoxy-acrylate m.p. 157°
Example 197 1o Methyl (E)-3-methoxy-2-fo-f(all-E)-4-phen~rl-1.3-butadienyll phenyll acrylate m.p. 165-167°
Example 198 ~E)- or (Z)-2-f2-f4-(3.5-bis-trifluoromethvl-phenyl)-buta-1,3-dienvllphenyil-3-methox~rylic acid methyl ester IR (KBr): 1703, 1630 cm-1 MS (EI): 456 (M) Example 199 ~E)- or (Z)-2-f2-f4-(2y4-bis-trifluoromethvl-phenyl)-buta-1.~3-2o dienyllphenyll-3-methoxy-acrylic acid methyl ester m.p. I76-177°
IR (KBr): 1703, 1630 cm-1 MS (EI): 456 (M) Example 200 Methyl-2-fo-f(all-E)-4-(m-bromophenyl)-1 3-butadien~phenyll 3 methoxvacrylic IR (KBr): 1701, 1626 cm-1 MS (EI): 399 (M) Example 201 Methyl (E)-2-fo-f(all-E)-4-(p-chlorophenyl)-1 3-butadienyl~phenyll-3-methoxyac late m.p. 209°
to Example 202 Methyl (E)-2-fo-f(all-E)-4- m-chlorophenyl)-13-butadienyllphenyll-3-methoxyacrylate m.p. 121-122°
Example 203 Methyl (E)-2-fo-f(all-E)-4-(o-bromophenyl)-1 3-butadienyl phen, l methoxyacrylate m.p. 150-151°
Example 204 Methyl (E)-3-methoxy-2-fo-f(all-E)-4-(3 4,5-trimethoxyphenvl)-13 2o butadienyll phenyll acrylate m.p. 98-102°
Example 205 Methyl (E)-2-fo-f(all-E)-4-(p-tert-butylnhenyl)-3-methyl-1 3-butadienvll-phenv113-methoxyacrylate IR (KBr): 1709, 1632 cm-1 MS (EI): 390 (M) Example 206 (Z)- or (E)-Methoxyimino-f2-f(lE.2E)-4-(2-trifluoromethyl~hen~)-buta-1,3-dien~phenyll-acetic acid methyl ester a) At 24°, BugSnH (0.56 ml, 2.1 mmol) was added to a solution of (2-ethynyl-phenyl)-methoxyimino-acetic acid methyl ester (151 mg, 0.7 mmol) and AIBN (cat.) in toluene (0.5 ml). After the mixture was stirred at 80° for 3.5 h, solvent was evaporated under reduced pressure and chromatography (hexane/ethylacetate 9:1) gave methoxyimino-[2-(E,Z)-(2-tributylstannanyl-vinyl)-phenyl]-acetic acid methyl ester (1:1 to mixture) (155 mg, 44%) as a yellowish liquid. IR (KBr): 1731, 1600 cm-1.
MS (EI): 508 (M).
b) A solution of 1-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene (989 mg, 3 mmol), and (Et)2POH (0.75 ml, 6 mmol) in Et3N (0.83 ml, 6 mmol) was stirred at 5° for 4 h. Hexane was added, and stirred for further 10 min. The mixture was extracted with hexane, washed with brine and dried over Na2S04. Evaporation of the solvent and chromatography (hexane) gave 1-(2-bromo-vinyl)-2-trifluoromethyl-benzene (674 mg, 90%) as a colorless liquid. IR (KBr): 1600, 940 cm-1 MS (EI): 251 (M).
2o c) At 24°, Pd[PPhg]4 (21 mg, 0.02 mmol) was added to a solution of 1-(1-bromo-vinyl)-2-trifluoromethyl-benzene (151 mg, 0.6 mmol) and methoxyimino-[2-(E,Z)-(2-tributylstannanyl-vinyl)-phenyl]-acetic acid methyl ester (304 mg, 0.6 mmol) in toluene (5 ml). The mixture was stirred at 110° for 5 h, cooled to room temperature, extracted with toluene, washed with brine, and dried over Na2S04. Evaporation of the solvent and chromatography (hexane/ ethylacetate 3:2) gave (Z)- or (E)-methoxyimino-[2-[( 1E,2E)-4-(2-trifluoromethylphenyl)-buta-1,3-dienyl] -phenyl]-acetic acid methyl ester (48 mg, 21%) as brown oil. IR (KBr):
1734, 1610 cm-1. MS (EI): 389 (M).

Example 251 (III) (E)-3-Methoxv-2-((E)-2-((R)- and (S)-3-(tetrahYdro-pyran 2 yloxy~
propenvll-phenvll-acrylic acid methyl ester (active intermediate) At 24°, Pd[PPh3]4 (58 mg, 0.05 mmol) was added to a solution of (E)-tributyl-[3-(R)- and (S)-(tetrahydro-pyran-2-yioxy)-propenyl]-stannane (2.2 g, 5.1 mmol) (E.J. Corey; J.W. Suggs, J. Org. Chem. 40, 2554, (1975)) and (E)-2-(2-bromo-phenyl)-3-methoxy-acrylic acid methyl ester {1.38 mg, 5.1 mmol) (EP 0307101 A2 890315) in toluene (20 ml).
The mixture was stirred at 110° for 2 days, cooled to room temperature, 1o extracted with toluene, washed with brine, and dried over Na2S04.
Evaporation of the solvent and chromatography (hexane/ethylacetate 9:1) gave (E)-3-methoxy-2-[(E)-2-[{R)- and (S)-3-{tetrahydro-pyran-2-yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (884 mg, 52%) as a white solid, m.p. 66-68°. IR (KBr): 1711, 1633 cm-1. MS (EI): 216 (M-MeOH-Dihydropyrane).
Example 252 (IV) ~E)-2-f2-(3-Hydroxy-propenylLuhenyll-3-metho -acrylic acid methyl ester (active intermediate) At 24°, toluene-4-sulfonic acid monohydrate (1.11 g, 0.4 mmol) was 2o added to a solution of (E)-3-methoxy-2-[(E)-2-[(R)- and (S)-3-(tetrahydro-pyran-2-yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (4.866 g, 14 mmol) in ethanol (70 ml). After the mixture was stirred for 6 h and neutralized with K2COg solution, the solvent was evaporated and the crude was dissolved in ethylacetate, washed with brine, water, and dried over Na2S04. Evaporation of the solvent gave (E)-2-[2-(3-hydroxy-propenyl)-phenyl]-3-methoxy-acrylic acid methyl ester (3.4 g, 93%) as a white solid, m.p. 78-80°. IR (KBr): 1683, 1619 cm-1. MS (EI): 216 (M-MeOH).
Example A
(E)-2-[2-(lE,3E)-4-[4,5-Dimethoxy-2-nitro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxyacrylic acid methyl ester can be formulated as the active ingredient according to methods known per se to give pharmaceutical preparations of the following composition:

_58_ 1. 500 m~ tablets Active ingredient 500 mg Powd. lactose 149 mg Polyvinylpyrrolidone 15 mg Dioctyl sodium sulphosuccinate 1 mg Na carboxymethylstarch 30 mg Magnesium stearate 5 m~
700 mg 2. 50 m~ tablets l0 Active ingredient 50 mg Powd. lactose 50 mg Microcrystalline cellulose 82 mg Na carboxymethylstarch 15 m~
200 mg 3. 100 m~ capsules Active ingredient 100.0 mg Powd. lactose 104.7 mg Corn starch ~ 70.0 mg Hydroxypropylmethylcellulose 10.0 mg 2o Dioctyl sodium sulphosuccinate 0.3 mg Talc 12.0 mg Magnesium stearate 3.0 m~

300.0 mg 4. 500 mg suppositories Active ingredient 500 mg Suppository mass ad 2000 mg 5. 100 mg soft gelatine capsules Active ingredient 100 mg Medium chain triglyceride 300 m~
400 mg

Claims (20)

Claims
1. The use of compounds of formulae IA or IB
wherein R1 is lower alkyl X is N or CH
R in IA is I a 1 wherein Y is S or O and A1 is phenyl, which may be substituted by one or more substituents, selected from halogen, lower alkoxy, lower alkyl, CF3, NO2, NH2, phenoxy or CF3-phenoxy; naphthyl; isothiazol-3-yl; thiazol-2-yl, optionally substituted by lower alkoxy alkoxyalkyl, lower alkyl, lower alkoxycarbonyl or lower acetoxyalkyl; thiadiazol-2-yl, optionally substituted by lower alkylthio, lower alkinylthio, cycloalkyl-alkylthio, CF3 or -NHC6H4CF3; quinoxalin-2-yl, optionally substituted by halogen or lower alkyl;
benzoxazol-2-yl; benzotriazine, optionally substituted by an oxo-group; and quinolin-2-yl;

or wherein R2 is hydrogen, lower alkoxycarbonyl, CF3, lower alkyl, cycloalkyl, lower alkoxyalkyl, lower alkylthioalkyl or lower alkoxy and A2 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, CF3, halogen, lower alkylthio, lower alkoxy or NO2;
-C(O)C6H5; -C(CH3)=CH-C6H4-lower alkyl;
-CH=CH-C6H5; pyridin-2-yl; pyridin-3-yl;
pyridin-4-yl; thiazol-5-yl, optionally substituted by lower alkyl; thien-3-yl, optionally substituted by lower alkyl; thien-2-yl, optionally substituted by halogen; quinolin-2-yl; naphthyl, benzo[b]thiophen-2-yl, optionally substituted by lower alkyl or halogen; or benzo [b] furan-2-yl;
or wherein W is S, O, NH or CH2;
R3 is hydrogen or lower alkyl and A3 is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran or phenyl, which may be substituted by one or more substituents, selected from halogen, CF3 or lower alkyl;
or wherein A4 is phenyl, which may be substituted by one or more substituents, selected from NO2, lower alkoxy, halogen, CF3, phenyloxy, styryl-phenyl or (2-CF3- or Cl-phenyl)-furan-2-yl; benzo(1,3]dioxol-5-yl, optionally substituted by halogen;
isoxazol-4-yl, optionally substituted by phenyl or lower alkoxyalkoxy; quinolin-3-yl; pyridin-2-yl;
pyridin-3-yl, pyridin-4-yl; furyl; thien-2-yl; thien-3-yl;
-C~C-C(CH3)3; -C~C-C6H5; indolizin-2-yl, optionally substituted by lower alkyl;
benzofuran-2-yl; benzopyran-3-yl or dihydrobenzo(b]thiophen-5-yl;

or wherein R4 is hydrogen or lower alkyl; and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO2, halogen, cyano or CF3; pyridin-2-yl;
pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl;
pyrrol-2-yl, optionally substituted by lower alkyl;
furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl;
thiazol-2-yl, optionally substituted by C6H4Cl;
thiazol-4-yl, optionally substituted by phenyl;
benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo [b] thiophen-3-yl;
or wherein A6 is phenyl, optionally substituted by CF3;
or wherein A7 is phenyl, optionally substituted by CF3;
or -(CH2)n-A8 Ia8 wherein n is 4 and A8 is phenyl, which may be substituted by one or more substituents, selected from CF3, halogen or -CH=N-OCH2-CO-OCH3; naphthyl or pyridin-4-yl;
or wherein A9 is phenyl, optionally substituted by CF3;
and wherein in formula IB
R6-R8 are hydrogen, lower alkyl or lower alkoxy and Z is hydrogen; lower alkoxy; lower alkyl; or halogen or wherein V is O, -N(CH3)-, -S- and B1 is phenyl, optionally substituted by halogen or alkyl; quinolin-8-yl; pyrimidin-2-yl;
-CH(CH3)-C6H5; or -CH2-C6H5;
or ~ wherein m is 0 or 1; and B2 is phenyl, optionally substituted by halogen, lower alkyl or CF3; or benzo[b]thiophen-5-yl;
or wherein B3 is phenyl, optionally substituted by CF3;
or wherein R5 is hydrogen, lower alkyl or lower alkoxyalkyl and B4 is phenyl, optionally substituted by CF3;
pyridin-2-yl; or thiazolin-5-yl, optionally substituted by lower alkyl;
or ~ wherein B5 is phenyl; -C~C-C(CH3)3; or thien-3-yl;
as well as pharmaceutically acceptable salts and possible stereoisomers as well as their racemates of compounds of formulae IA and IB as therapeutically active substances.
2. The use according to claim 1 against chloroquine-sensitive and chloroquine-resistant pathogens and respectively, for the production of corresponding medicaments.
3. The use according to claims 1 to 2 of compounds of formula IA
from the group of compounds wherein R1, X, Y and A1 have the significances given in claim 1.
4. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X, R2 and A2 have the significances given in claim 1.
5. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X, R3, W and A3 have the significances given in claim 1.
6. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X and A4 have the significances given in claim 1.
7. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X, R4 and R5 have the significances given in claim 1.
8. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X and A6 have the significances given in claim 1.
9. The use according to claims 1 and 2 of compounds of formula IA
from the group of compounds wherein R1, X and A7 have the significances given in claim 1.
10. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds wherein R1, X, n and A8 have the significances given in claim 1.
11. The use according to claims 1 and 2 of compounds of formula IA from the group of compounds wherein R1. X and A9 have the significances given in claim 1.
12. The use according to claims 1 and 2 of compounds of formula IB from the group wherein R1, X, V and B1 have the significances given in claim 1.
13. The use according to claims 1 and 2 of compounds of formula IB from the group wherein R1, X, m and B1 have the significances given in claim 1.
14. The use according to claims 1 and 2 of compounds of formula IB from the group wherein R1, X and B3 have the significances given in claim 1.
15. The use according to claims 1 and 2 of compounds of formula IB from the group wherein R1, X, R5 and B4 have the significances given in claim 1.
16. The use according to claims 1 and 2 of compounds of formula IB from the group wherein R1, X and B5 have the significances given in claim 1.
17. The use according to claims 1 and 2 of compounds of formula IB, wherein R6, R7 and R8 have the significances given in claim 1 and Z
is lower alkoxy, lower alkyl, halogen or hydrogen.
18. Compounds of formula wherein R1 is lower alkyl, X is N or CH, R4 is hydrogen or lower alkyl and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO2, halogen, cyano or CF3; pyridin-2-yl; pyridin-4-yl;
quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl;
thien-3-yl, optionally substituted by halogen and lower alkyl; thiazol-2-yl, optionally substituted by C6H4C1;
thiazol-4-yl, optionally substituted by phenyl;
benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo[b]thiophen-3-yl;
as well as their pharmaceutically acceptable salts and possible stereoisomers as well as their racemates.
19. A medicament, especially for the treatment and/or prevention of malaria, containing one or more compounds according to any one of claims 1-16 and at least one therapeutically inert excipient.
20. The invention as hereinbefore described.
CA002294931A 1997-07-09 1998-07-06 .beta.-alkoxyacrylates against malaria Abandoned CA2294931A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP97111607 1997-07-09
EP97111607.4 1997-07-09
PCT/EP1998/004162 WO1999002150A1 (en) 1997-07-09 1998-07-06 β-ALKOXYACRYLATES AGAINST MALARIA

Publications (1)

Publication Number Publication Date
CA2294931A1 true CA2294931A1 (en) 1999-01-21

Family

ID=8227034

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002294931A Abandoned CA2294931A1 (en) 1997-07-09 1998-07-06 .beta.-alkoxyacrylates against malaria

Country Status (15)

Country Link
US (1) US6084120A (en)
EP (1) EP0996439B1 (en)
JP (1) JP2002511881A (en)
KR (1) KR20010014339A (en)
CN (1) CN1109544C (en)
AT (1) ATE230718T1 (en)
AU (1) AU748990B2 (en)
BR (1) BR9810556A (en)
CA (1) CA2294931A1 (en)
DE (1) DE69810629T2 (en)
DK (1) DK0996439T3 (en)
ES (1) ES2189206T3 (en)
PT (1) PT996439E (en)
TR (1) TR200000005T2 (en)
WO (1) WO1999002150A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000641A2 (en) * 2000-06-28 2002-01-03 Eli Lilly And Company Spla2 inhibitors
CN100443463C (en) * 2005-06-28 2008-12-17 沈阳化工研究院 Substituted p-trifluoromethyl phenyl ether compound and its prepn and application
US20100234366A1 (en) * 2006-03-29 2010-09-16 Bsf Se Use of Strobilurins for the Treatment of Disorders of Iron Metabolism
US8772290B2 (en) 2010-04-21 2014-07-08 Oscotech Inc. Alpha-arylmethoxyacrylate derivative, preparation method thereof, and pharmaceutical composition containing same
US9895346B2 (en) 2013-08-27 2018-02-20 Sinochem Corporation Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs
CN103601716A (en) * 2013-11-20 2014-02-26 厦门大学 Benzothiophene substituted oxime ether compound and preparation method and application thereof
CN103980179A (en) * 2014-05-29 2014-08-13 厦门大学 Indole-substituted oxime ether compounds as well as preparation method and application thereof
US10519098B2 (en) * 2014-10-21 2019-12-31 Council Of Scientific & Industrial Research Aromatic derivatives as anti-malarial
WO2016193267A1 (en) * 2015-06-02 2016-12-08 Syngenta Participations Ag Mosquito vector control compositions, methods and products utilizing same

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ213630A (en) * 1984-10-19 1990-02-26 Ici Plc Acrylic acid derivatives and fungicidal compositions
DE3519280A1 (en) * 1985-05-30 1986-12-04 Basf Ag, 6700 Ludwigshafen STYLE DERIVATIVES AND FUNGICIDES THAT CONTAIN THESE COMPOUNDS
GB8617648D0 (en) * 1986-07-18 1986-08-28 Ici Plc Fungicides
ES2052696T5 (en) * 1987-02-09 2000-03-01 Zeneca Ltd FUNGICIDES.
YU47288B (en) * 1987-07-11 1995-01-31 Schering Agrochemicals Limited ACRYLATE FUNGICIDES AND THE PROCEDURE FOR THEIR PRODUCTION
EP0506149B1 (en) * 1988-11-21 1998-08-12 Zeneca Limited Intermediate compounds for the preparation of fungicides
KR100187541B1 (en) * 1988-12-29 1999-06-01 쟝-자크 오가이; 롤란트 보러 Methyl esters of aldimino- or ketimino-oxy-ortho-tolylacrylic acid, manufacturing process and fungicides containing them
DE3901607A1 (en) * 1989-01-20 1990-08-16 Basf Ag SULFURY ACRYLIC ACID ESTERS AND FUNGICIDES CONTAINING THEM
ES2067012T3 (en) * 1989-12-14 1995-03-16 Ciba Geigy Ag HETERO CYCLIC COMPOUNDS.
PH11991042549B1 (en) * 1990-06-05 2000-12-04
DK0669319T3 (en) * 1990-06-27 1999-02-08 Basf Ag O-benzyloxymeters and plant protection products containing these compounds
DE4028391A1 (en) * 1990-09-07 1992-03-12 Basf Ag (ALPHA) -ARYLACRYLIC ACID DERIVATIVES, THEIR PRODUCTION AND USE FOR CONTROLLING PLANTS AND MUSHROOMS
DE4029192A1 (en) * 1990-09-14 1992-03-19 Basf Ag USE OF (ALPHA) -ARYLACRYLIC ACID DERIVATIVES FOR CONTROLLING PESTS
FR2670781B1 (en) * 1990-12-21 1994-09-16 Roussel Uclaf NOVEL DERIVATIVES OF ALPHA-METHYLENE 6-STYRYL PHENYL ACRYLIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS PESTICIDES.
FR2670782A1 (en) * 1990-12-24 1992-06-26 Valoris Chimie Fine Lab Acridine crown ethers and acridinone crown ethers
DE4117371A1 (en) * 1991-05-28 1992-12-03 Basf Ag ANTIMYCOTIC AGENTS CONTAINING PHENYL ACIDSEED DERIVATIVES
TW224042B (en) * 1992-04-04 1994-05-21 Basf Ag

Also Published As

Publication number Publication date
JP2002511881A (en) 2002-04-16
EP0996439B1 (en) 2003-01-08
AU748990B2 (en) 2002-06-13
TR200000005T2 (en) 2000-09-21
EP0996439A1 (en) 2000-05-03
DE69810629T2 (en) 2003-10-16
KR20010014339A (en) 2001-02-26
US6084120A (en) 2000-07-04
DE69810629D1 (en) 2003-02-13
WO1999002150A1 (en) 1999-01-21
CN1109544C (en) 2003-05-28
BR9810556A (en) 2000-08-15
AU8441198A (en) 1999-02-08
PT996439E (en) 2003-04-30
ATE230718T1 (en) 2003-01-15
DK0996439T3 (en) 2003-05-05
CN1262620A (en) 2000-08-09
ES2189206T3 (en) 2003-07-01

Similar Documents

Publication Publication Date Title
JP4795022B2 (en) Novel antifungal agent containing a heterocyclic compound
DE69916881T2 (en) ANTIHYPERTRIGLYCERIDEMIC, ANTIHYPERGLYCEMIC, ANTIANGIOGENIC AND WOUND HEALING SUBSTITUTED INDOLALCANIC ACID
US20150313881A1 (en) Therapeutic Methods for Type I Diabetes
AU2017204665A1 (en) Pyridine derivative
CA2294931A1 (en) .beta.-alkoxyacrylates against malaria
TWI387456B (en) Combination of ferroquine and an artemisinin derivative for the treatment of malaria
EP1102535A2 (en) Compounds and methods
CN101484449A (en) Integrase inhibitors 3
JP6356334B2 (en) Novel indene derivative, preparation method thereof, and pharmaceutical composition for preventing or treating retinal diseases containing the same as an active ingredient
DE112012004878T5 (en) Heterocyclic dihydro five-membered ketone derivatives as DHODH inhibitor and their use
CN101622229A (en) Novel pyrrole derivative having ureido group and aminocarbonyl group as substituents
WO2003006443A2 (en) 2- 4-(naphtalin-2-yl)-thiazol-2-ylaminocarbonyl benzoic acid and 2- 4-(naphtalin-2-yl)-pyrimidin-2-ylaminocarbonyl benzoic acid and additional compounds serving as telomerase inhibitors for use in tumor therapy
US20030055263A1 (en) Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
Jain et al. Antimalarial activities of ring-substituted bioimidazoles
JPS5817760B2 (en) Spiro-furanohydantoin derivatives
MXPA00000284A (en) &bgr;-ALKOXYACRYLATES AGAINST MALARIA
US7064139B2 (en) Method for treating retroviral infections
AU2017204652B2 (en) Treatment of Type I and Type II diabetes
AU2003207589B2 (en) 2-Aminothiazole Allosteric Enhancers of A1 Adenosine Receptors
EP0169502A2 (en) 2-Benzyl-4-(2-morpholino)-4-Pyriol) Thiazole
JPS63104959A (en) Alpha-(phenylalkyl)pyridinealkanol derivative
AU2019223911A1 (en) Treatment of liver diseases
JP2003034640A (en) Antimalarial drug containing tetracyclic hetero compound
CN109912576B (en) Cyclic or spirocyclic diamine pyrimidine-hydroxamic acids and their use
US8653095B2 (en) Small molecules with antimalarial activity

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued